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Ref Type Journal Article
PMID (26775591)
Authors Kodityal S, Elvin JA, Squillace R, Agarwal N, Miller VA, Ali SM, Klempner SJ, Ou SH
Title A novel acquired ALK F1245C mutation confers resistance to crizotinib in ALK-positive NSCLC but is sensitive to ceritinib.
Journal Lung cancer (Amsterdam, Netherlands)
Vol 92
Issue
Date 2016 Feb
URL
Abstract Text The emergence of acquired anaplastic lymphoma kinase (ALK) resistant mutations is a common molecular mechanism underpinning disease progression during crizotinib treatment of ALK-positive (ALK+) non-small cell lung cancer (NSCLC) patients. Identifying acquired resistance mutations in ALK is paramount for tailoring future therapy with second generation ALK inhibitors and beyond. Comprehensive genomic profiling using hybrid-capture next generation sequencing has been successful in identifying acquired ALK resistance mutations. Here we described the emergence of an ALK F1245C mutation in an advanced ALK+ NSCLC patient (EML4-ALK variant 3a/b) who developed slow disease progression after a durable response to crizotinib. The patient was eventually switched to ceritinib with on-going clinical response. This is the first patient report that ALK F1245C is an acquired resistance mutation to crizotinib that can be overcome by ceritinib.

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Molecular Profile Treatment Approach
EML4 - ALK ALK F1245C Ceritinib
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
EML4 - ALK ALK F1245C lung non-small cell carcinoma predicted - resistant Crizotinib Case Reports/Case Series Actionable In a clinical case study, a non-small cell lung cancer patient harboring EML4-ALK variant 3 demonstrated an initial response to treatment with Xalkori (crizotinib), but progressed after 27 months and was found to have acquired ALK F1245C (PMID: 26775591). 26775591
EML4 - ALK ALK F1245C lung non-small cell carcinoma sensitive Ceritinib Case Reports/Case Series Actionable In a clinical case study, a non-small cell lung cancer patient harboring EML4-ALK variant 3 that demonstrated resistance to treatment with Xalkori (crizotinib) after acquisition of ALK F1245C, achieved a complete radiographic response with no evidence of progression at 6 months following treatment with Zykadia (ceritinib) (PMID: 26775591). 26775591